Biology subjects

McCabe, J. T.

Publications and source records attributed to McCabe, J. T..

3 recordsLinked to original sources

bioRxiv2025

A spatial gene expression signature of the mouse brain post-injury at the focal point of contusion

Traumatic brain injury (TBI) results from a primary injury that impacts the brain in a spatially-dependent manner. Here we investigated the topographical relationship of early transcriptional responses to a single, focal TBI in mice by controlled cortical impact (CCI). Guided by the presence of the anterior commissure (AC) in coronal sections at the rostro-caudal point of impact, we compared gene expression changes in the neocortex (CTX) and corpus callosum-external capsule (CC-EC), striatum (STR) and AC. Injury-induced gene expression changes were detected in the CTX, CC-EC and STR but not AC and were principally segregated based on cytoarchitecture, and secondarily by proximity to the site of impact. Additionally, unbiased spatial clustering revealed a positive relationship between proximity to the impact and the number of acutely differentially expressed genes within the laminar CTX. Gene pathways for interferon gamma response and for leukocyte-mediated migration and immunity were acutely enhanced across the injured CTX, CC-EC and STR. Within 1-week post-injury, transcriptional responses to injury in the CTX and CC-EC included gene pathways for adaptive T- and B-cell mediated immunity, whereas gene expression changes in the STR were largely resolved. Next, we examined the effects of systemic depletion of neutrophils and monocytes on spatial gene expression changes in the injured brain. This led to the upregulation of gene pathways functioning in synaptic transmission and an alternating down- and then upregulation of genes functioning in ribosomal messenger RNA translation and aerobic metabolism in mitochondria. These data suggest infiltrating neutrophils and monocytes play an evolving, multifaceted role in modulating the metabolic, transcriptional, and synaptic activity of brain tissue post-injury.

neuroscience↗

bioRxiv2025

Improved Injury Detection Through Harmonizing Multi-Site Neuroimaging Data after Experimental TBI: A Translational Outcomes Project in NeuroTrauma (TOP-NT) Consortium Study

Multi-site neuroimaging studies have become increasingly common in order to generate larger samples of reproducible data to answer questions associated with smaller effect sizes. The data harmonization model NeuroCombat has been shown to remove site effects introduced by differences in site-related technical variance while maintaining group differences, yet its effect on improving statistical power in pre-clinical models of CNS disease is unclear. The present study examined fractional anisotropy data computed from diffusion weighted imaging data at 3 and 30 days post-controlled cortical impact injury from 184 adult rats across four sites as part of the Translational-Outcome-Project-in-Neurotrauma (TOP-NT) Consortium. Findings confirmed prior clinical reports that NeuroCombat fails to remove site effects in data containing a high proportion-of-outliers (>5%) and skewness, which introduced significant variation in non-outlier sites. After removal of one outlier site and harmonization using a global sham population, harmonization displayed an increase in effect size in data that displayed group level effects (p<0.01) in both univariate and voxel-level volumes of pathology. This was characterized by movement toward similar distributions in voxel measurements (Kolmogorov-Smirnov p<<0.001 to >0.01) and statistical power increases within the ipsilateral cortex. Harmonization improved statistical power and frequency of significant differences in areas with existing group differences, thus improving the ability to detect regions affected by injury rather than by other confounds. These findings indicate the utility of NeuroCombat in reproducible data collection, where biological differences can be accurately revealed to allow for greater reliability in multi-site neuroimaging studies. Significance StatementThis project demonstrates the utility of NeuroCombat in reducing site effects in multi-site rodent imaging. We also demonstrate that harmonization improves the ability to distinguish between sham and injured rats at the voxel level and increase statistical power and effect size in areas of injury. Multi-center studies are becoming more common to allow for increased efficiency in data collection, and with conservative approaches and analysis into the datasets, NeuroCombat can be utilized to improve study reliability and reproducibility.

neuroscience↗

bioRxiv2022

Persistent Hypersomnia Following Repetitive Mild Experimental Traumatic Brain Injury: Roles of Chronic Stress and Sex Differences

Traumatic brain injury (TBI) is often more complicated than a single head injury. An extreme example of this point may be military service members who experience a spectrum of exposures over a prolonged period under stressful conditions. Understanding the effects of complex exposures can support proper evaluation and care for patients experiencing persistent symptoms. We designed a longitudinal series of non-invasive procedures in adult mice to evaluate the effects of prolonged mild exposures. We assessed anxiety, depression, and sleep-wake dysfunction as symptoms that can impact long term outcomes after mild TBI. Unpredictable chronic mild stress (UCMS) was generated from a variable sequence of environmental stressors distributed within each of 21 days. Subsequently, mice received a mild blast combined with closed-head mild TBI on five days at 24-hour intervals. TBI components were either five linear force impacts, or a novel alternating repetitive mild TBI (Ar-mTBI) model of linear and rotational (CHIMERA) impacts over five days to produce diffuse pathology. In males and females, UCMS induced anxiety without depressive behavior. Persistent hypersomnia, specifically increased sleep during the active dark period, was found through 6-12 month time points in male mice receiving UCMS with repetitive blast plus TBI events, or surprisingly after UCMS alone. Sleep-wake dysfunction was not found with TBI events alone and was not found in females under any conditions. These results identify prolonged stress and sex differences as important considerations for sleep-wake dysfunction. Furthermore, this reproducible hypersomnia is similar to excessive daytime sleepiness reported in patients, which may inform treatments.

neuroscience↗